A primary organism involved in the development and progression of periodontal disease is the periodontopathogen, Porphyromonas gingivalis. This bacterium utilizes an arsenal of virulence factors to avoid host defense, allowing for its growth and proliferation at infected sites. Among these factors are proteolytic enzymes, which appear to be involved in the deregulation of cascade pathways, the inactivation of plasma proteinase inhibitors, and the disruption of chemotactic processes, all to the benefit of the invading organism. Many of these enzymes have been isolated and characterized in this laboratory, and it seems clear that inhibitors developed against them would significantly reduce the pathological symptoms associated with periodontitis. Nevertheless, in some types of periodontal disease, especially its early phase, other bacterial pathogens are likely to be involved. For these reasons, the Specific Aims of this project are as follows: 1) to expand the model we have developed which directly points to major roles for P. gingivalis proteinases in the pathological hallmarks of periodontal disease (bleeding on probing, swelling, tissue resorption, bone loss), 2), to initiate experiments to determine if other bacterial pathogens which are found at the early stages of periodontal disease also utilize proteolytic enzymes for host defense evasion, and 3) to screen for and purify low and high molecular weight proteinase inhibitors which may be synthesized by other oral organisms for the possible control of P. gingivalis growth and proliferation. Our long-term goals are to determine whether the mechanisms used by P. gingivalis to avoid host defense are a general process that other pathogens have adopted and to develop inhibitors against such enzymes in order to control or eradicate bacterial infections.